Adiponectin is an adipokine that promotes insulin sensitivity. Heterodimers of retinoid X receptor (RXR) and the nuclear receptor PPAR-gamma activate the adiponectin promoter when stimulated by thiazolidinediones, synthetic PPAR-gamma ligands that induce insulin sensitization and are widely used in the treatment of type 2 diabetes mellitus. IGFBP-3 binds to RXR and inhibits transcription activation by several other RXR:nuclear receptor heterodimers. This suggested that IGFBP-3, by binding to RXR, also might inhibit the stimulation of adiponectin transcription by RXR:PPAR-gamma heterodimers. We studied IGFBP-3 regulation of thiazolidinedione-induced adiponectin promoter activity using mouse embryo fibroblasts stably transfected with PPAR-gamma-2. The cells were transfected with a luciferase reporter gene under the control of the adiponectin promoter, and were treated with the thiazolidinedione, rosiglitazone. Rosiglitazone induced adiponectin promoter activity. Recombinant human IGFBP-3 inhibited both basal and rosiglitazone-induced adiponectin promoter activity. Studies are in progress using an IGFBP-3 mutant that does not bind RXR to determine whether IGFBP-3 binding to RXR is required for it to inhibit adiponectin promoter activity. Inhibition of adiponectin transcription by IGFBP-3 represents a potential mechanism by which IGFBP-3 can contribute to the development of insulin resistance.